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Genetic variants associated with breast cancer risk for Ashkenazi Jewish women with strong family histories but no identifiable BRCA1/2 mutation

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Abstract

The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome-wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations. This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts comprised 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation. A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. In addition, six previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, three novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and three previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74. Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations.

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Acknowledgments

The authors gratefully acknowledge the generous contribution of the patients who participated in this study. We also wish to thank Gord Glendon, Teresa Selander, Nayana Weerasooriya and members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. We would like to thank Dr. Susan Love Army of Women, Peter Pressman from Weill Cornell Medical College, and Ina Ratner of Maimonides Medical Center for their help with recruitment. Finally we would like to thank Dr. Bert Gold from the National Cancer Institute–Frederick for his help with obtaining data for the MSKCC dataset.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics statement

This study was performed under the NYU School of Medicine Institutional Review Board-approved protocol, “Genetic Modifiers of Breast and Ovarian Cancer Risk” (07-333).

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Authors and Affiliations

  1. Department of Surgery, New York University Langone Medical Center, New York, NY, USA

    Erica S. Rinella, Freya Schnabel & Daniel Roses

  2. Division of Biostatistics, New York University School of Medicine, New York, NY, USA

    Yongzhao Shao

  3. Department of Pathology, Albert Einstein College of Medicine, Ullman 715, 1300 Morris Park Rd, Bronx, NY, 10461, USA

    Lauren Yackowski, Christopher L. Campbell & Harry Ostrer

  4. Kolkata Zonal Laboratory, National Environmental Engineering Research Institute, Kolkata, India

    Sreemanta Pramanik

  5. Department of Pediatrics, Columbia University Medical Center, New York, NY, USA

    Saurav Guha, Charles LeDuc & Wendy K. Chung

  6. Department of Obstetrics and Gynecology and Women’s Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Susan D. Klugman

  7. Department of Epidemiology, Mailman School of Public Health of Columbia University, New York, NY, USA

    Mary Beth Terry & Ruby T. Senie

  8. Department of Molecular Genetics, University of Toronto, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

    Irene L. Andrulis

  9. Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA

    Mary Daly

  10. Cancer Prevention Institute of California, Fremont, CA, USA

    Esther M. John

  11. Stanford University School of Medicine and Stanford Cancer Institute, Stanford, CA, USA

    Esther M. John

  12. Department of Medicine, New York University Langone Medical Center, New York, NY, USA

    Ruth Oratz

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  1. Erica S. Rinella
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  2. Yongzhao Shao
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  4. Sreemanta Pramanik
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Correspondence to Harry Ostrer.

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Rinella, E.S., Shao, Y., Yackowski, L. et al. Genetic variants associated with breast cancer risk for Ashkenazi Jewish women with strong family histories but no identifiable BRCA1/2 mutation. Hum Genet 132, 523–536 (2013). https://doi.org/10.1007/s00439-013-1269-4

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  • DOI: https://doi.org/10.1007/s00439-013-1269-4

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